The present invention relates generally to antibiotic mitosane compounds and to their use in the treatment of neoplastic disease states in animals.
The disclosures of my U.S. Pat. Nos. 4,268,676 and 4,460,599; my co-pending U.S. patent application Ser. No. 264,187 filed May 15, 1981; and my co-pending U.S. patent application Ser. No. 464,612 filed Feb. 7, 1983, are specifically incorporated by reference herein to the extent that they may provide essential and nonessential material relating to the present invention.
Briefly summarized, said U.S. Pat. Nos. 4,268,676 and 4,460,599 set forth a statement of the background of the ongoing search in the art for new and useful compounds which are structurally related to the mitomycins, which possess antibiotic activity, which have low toxicity and which display a substantial degree of antitumor activity in animals. More particularly, they disclose new compounds of the formula I, ##STR2##
wherein: Y is hydrogen or lower alkyl; and X is a thiazolamino radical, a furfurylamino radical or a radical of the formula, ##STR3## in which R, R.sup.1 and R.sup.2 are the same or different and selected from the group consisting of hydrogen and lower alkyl, and R.sup.3 is selected from the group consisting of lower alkenyl, halo-lower alkenyl, lower alkynyl, lower alkoxycarbonyl, thienyl, formamyl, tetrahydrofuryl and benzene sulfonamide.
Said U.S. patents also disclose novel methods for treatment of neoplastic disease states in animals, which methods comprise administering a therapeutically effective amount of a compound of the formula Ia, ##STR4## wherein: Y is hydrogen or lower alkyl; and Z is a thiazolamino radical, a furfurylamino radical, a cyclopropylamino radical, a pyridylamino radical, or a radical of the formula, ##STR5## in which R.sup.4, R.sup.5, and R.sup.6 are the same or different and selected from the group consisting of hydrogen and lower alkyl, and R.sup.7 is selected from the group consisting of lower alkenyl, halo-lower alkenyl, lower alkynyl, lower alkoxy-carbonyl, halo-lower alkyl, hydroxy-lower alkyl, pyridyl, thienyl, formamyl, tetrahydrofuryl, benzyl, and benzene sulfonamide.
Co-pending U.S. patent application Ser. No. 264,187 also discloses compounds with a substantial degree of antitumor activity in animals of the following formula IIa, ##STR6##
wherein: Y is hydrogen or lower alkyl; and Z is a lower alkoxy substituted quinolinylamino radical, a cyano substituted pyrazolylamino radical or a mono- or di-lower alkyl substituted thiazolamino radical, or
a nitrogen-containing heterocyclic radical selected from the group consisting of 1-pyrrolinyl, 1-indolinyl, N-thiazolidinyl, N-morpholinyl, 1-piperazinyl, and N-thiomorpholinyl radicals, or
a cyano, phenyl, carboxamido or lower alkoxycarbonyl substituted 1-aziridinyl radical, or
a lower alkyl, formyl or acetylphenyl substituted 1-piperazinyl radical, or
an hydroxy or piperidyl substituted 1-piperidyl radical, or
a lower alkoxy, amino or halo substituted pyridyl-amino radical, or
a carboxamido, mercapto or methylenedioxy substituted anilino radical, or
a radical of the formula, ##STR7##
wherein R is hydrogen or lower alkyl and R' is a nitrogen-containing heterocyclic radical selected from the group consisting of quinuclidinyl, pyrazolyl, 1-triazolyl, isoquinolinyl, indazolyl, benzoxazolyl, thiadiazolyl and benzothiadiazolyl, and lower alkyl and halo substituted derivatives thereof, or
a butyrolactonyl radical, or
an adamantyl radical, or
a mono-lower alkoxy substituted phenyl radical, or
a substituted lower alkyl radical selected from the group consisting of mercapto lower alkyl, carboxy lower alkyl, mono-, di- and tri-lower alkoxy lower alkyl, lower alkyl thio lower alkyl and lower alkoxycarbonyl substituted derivatives thereof, cyano lower alkyl, mono-, di- and tri-lower alkoxy phenyl lower alkyl, phenyl cyclo lower alkyl, 1-pyrrolidinyl lower alkyl, N-lower alkyl pyrrolidinyl lower alkyl, N-morpholinyl lower alkyl, and lower dialkylamino lower alkyl.
Co-pending U.S. patent application Ser. No. 464,612 also discloses compounds for use in treatment of neoplastic disease states in animals of the formula IIIa, ##STR8##
wherein: Y is hydrogen or lower alkyl; and Z is
an hydroxy substituted 1-pyrrolidinyl radical, or
a lower alkyl substituted piperidyl radical, or
a 1-piperazinyl radical or an acetamino, acetyl, carbamido, cyano, carboxy lower alkylamino, di-lower alkoxy, nitro, sulfamyl, or lower alkyl substituted anilino radical, or
a radical of the formula, ##STR9##
wherein R is hydrogen or lower alkyl and R.sup.1 is a nitrogen containing heterocyclic radical selected from the group consisting of amino substituted triazolyl, lower alkyl substituted isothiazolyl, benzothiazolyl, and nitro and halo substituted derivatives of benzothiazolyl, or R.sup.1 is
a substituted lower alkyl radical selected from the group consisting of amino lower alkyl, lower alkylamino lower alkyl, hydroxy lower alkylamino lower alkyl, hydroxy lower alkoxy lower alkyl, imidazolyl lower alkyl, nitro substituted imidazolyl lower alkyl, mono- and di-hydroxy phenyl lower alkyl, nitro substituted pyridylamino lower alkyl, piperazinyl lower alkyl, and pyridyl ethyl.
The synthesis and biological evaluation of a series of 7-alkoxymitosanes including 7-ethoxy, 7-n-propoxy, 7-i-propoxy, 7-n-butoxy, 7-i-butoxy, 7-sec-butoxy, 7-n-amyloxy, 7-i-amyloxy, 7-n-hexyloxy, 7-cyclohexyloxy, 7-n-heptyloxy, 7-n-octyloxy, 7-n-decyloxy, 7-stearyloxy, 7-(2-methoxy)ethoxy, and 7-benzyloxy derivatives of mitomycin A was reported in Urakawa, C., et al., J. Antibiotics, 33: 804-809 (1980). Also shown is the 7-i-propoxy derivative of mitomycin B. Most of these compounds displayed antibacterial activities against Gram-positive and Gram-negative bacterial strains and strong inhibition of growth of HeLa S-3 cells in vitro.
Also pertinent to the background of the present invention are the following references: Cosulich, et al., U.S. Pat. No. 3,332,944; Matsui, et al., U.S. Pat. No. 3,410,867; Nakano, et al., U.S. Pat. No. 4,231,936; Matsui, et al., U.S. Pat. No. 3,429,894; Remers, U.S. Pat. No. 4,268,676; Matsui, et al., U.S. Pat. No. 3,450,705; Matsui, et al., U.S. Pat. No. 3,514,452; and Imai, et al., Gann, 71: 560-562 (1980).